Within the past decade, opioid drug abuse has dramatically increased to unprecedented levels. The illicit opioid heroin as well as the prescription opioids oxycodone (Oxycotin) and hydrocodone (Vicodin) are the most commonly abused opioids, and they incur a large social and economic cost to society. More than ever before, effective therapies are needed to combat the destructive increase in opioid abuse. Because these drugs are highly addictive, traditional pharmacological treatments such as methadone substitution fall short at preventing relapse. Fortunately, great strides have been made in identifying active vaccination strategies for opioid abuse. Drug-conjugate vaccines can elicit long-lasting, high-affinity antibodies which selectively neutralize administered drug doses without side-effects. The Janda laboratory has developed a heroin conjugate vaccine that can successfully attenuate heroin intake in rat self-administration models. Furthermore, the vaccine shifts the heroin ED50 by greater than 20-fold in mouse antinociceptive testing compared to unvaccinated animals. Lastly, the vaccine remains effective for over 8 months in mice with booster vaccines without producing any observable adverse reactions. Due to the promising nature of this therapeutic approach, additional studies are warranted to uncover the full potential of opioid vaccines. In sum, four aims within two phases will be implemented: UH2 Phase. Aim1. Refine the heroin vaccine formulation to produce optimal efficacy and safety. Aim 2. Adapt heroin vaccine design elements to other opioids. Oxy and hydrocodone share structural features with heroin that beget compatibility with our heroin immunoconjugate scaffold, enabling access to vaccines against these opioids. Aim 3. Non-human primate testing is essential for determining whether the heroin vaccine can be translated to humans. Within this aim we will evaluate the heroin vaccine in a pilot study in rhesus macaques. Heroin schedule controlled responding (SCR) and heroin pharmacokinetics (PK) will be conducted to accurately gauge the efficacy and compatibility of the heroin vaccine in primates. UH3 Phase. Within this phase we will seek to conduct translational opioid vaccine studies. Thus, within Aim 4 we will conduct a series of studies that will be broken into three sub-aims including: 4A. Optimize immunoconjugate preparation protocols, and investigate vaccine toxicology and long-term stability. 4B. Examine the vaccine in self-administration models in rhesus macaques; a heroin versus food choice procedure will employed to determine if the heroin vaccine can attenuate drug intake under a variety of conditions that are representative of what human drug addicts experience. 4C. Perform pilot studies investigating Aim 2 oxy and hydrocodone vaccines in monkey SCR and PK studies. Overall our aims align with the goals of advancing opioid vaccine candidates toward clinical trials, while also establishing new testing paradigms for future addiction therapies.